A novel peptide capable of reproducing several of the biologic effects of parathyroid hormone (PTH) has recently been purified and cloned from several human malignancies associated with hypercalcemia. This PTH-like peptide (PLP) resembles PTH in its ability to stimulate renal and skeletal adenylate cyclase, and to produce increased bone resorption, hypercalcemia, and decreased renal phosphate transport. Its primary structure also bears some similarity to that of PTH, although this is largely limited to the amino-terminal 1-13 residues of the peptides. We propose to compare the initial cellular mechanisms of action of PTH and PLP, using their biologically active amino-terminal fragments. We will: 1) determine the ability of PLP to reproduce the actions of PTH on the adenylate cyclase-coupled PTH receptor in canine renal membranes, opossum kidney (OK) cells, and UMR-106 osteoblast-like osteosarcoma cells. This will be accomplished through comparative receptor binding and photoaffinity-labeling studies using biologically active, 125I-labeled synthetic PTH and PLP peptides. In addition, the molecular mechanism of receptor- adenylate cyclase coupling induced by PLP binding will be elucidated; and 2) determine the extent to which PLP reproduces the effect of PTH on cytosolic free calcium and phosphoinositide- specific phospholipase C in OK cells and in UMR-106 cells. In addition, the possible importance of this signaling pathway to the physiologic effect of PTH and PLP on OK cells, inhibition of sodium-dependent phosphate transport. Will be determined. Successful completion of these studies will provide new insights into the molecular basis for the PTH-like actions of PLP. Furthermore, new light will be shed on the importance of distinct signaling pathways, and conceivably distinct receptors, in the actions of these peptides.